Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002)

Background Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients. Methods We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed PTCL entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria. Results Between July 12, 2018, and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At the data cutoff date (August 15, 2020), the median follow-up was 4.06 (range 0.30–22.9) months. For 89 patients in FAS, 36 achieved objective response (40.4%, 95% CI 30.2–51.4), of which 13 (14.6%) were complete response and 23 (25.8%) had partial response assessed by IRRC. The median duration of response (DOR) was 11.4 (95% CI 4.8 to not reached) months per IRRC. Patients with PD-L1 expression ≥ 50% derived more benefit from geptanolimab treatment compared to < 50% ones (ORR, 53.3% vs. 25.0%, p = 0.013; median PFS 6.2 vs. 1.5 months, p = 0.002). Grade ≥ 3 treatment-related adverse events occurred in 26 (25.5%) patients, and the most commonly observed were lymphocyte count decreased (n = 4) and platelet count decreased (n = 3). Serious adverse events were observed in 45 (44.1%) patients and 19 (18.6%) were treatment related. Conclusions In this study, geptanolimab showed promising activity and manageable safety profile in patients with r/r PTCL. Anti-PD-1 antibody could be a new treatment approach for this patient population. Trial registration: This clinical trial was registered at the ClinicalTrials.gov (NCT03502629) on April 18, 2018.


Introduction
According to the 2016 World Health Organization classification of lymphoid neoplasms [1], peripheral T cell lymphomas (PTCLs) were classified into 27 distinct subtypes. This heterogeneous disease entity accounts for around 25% of non-Hodgkin lymphoma (NHL) patients in China and about 10% in USA and Europe [2,3]. Due to its heterogeneity and rarity, most of the clinical studies conducted in PTCL were retrospective with a small sample size in which the treatment regimens largely followed B cell NHL. However, worse prognosis was associated with PTCLs when compared to B cell NHL as 5-year overall survival (OS) rate was only 32% in most common PTCL subtypes (PTCL not otherwise specified [PTCL-NOS], angioimmunoblastic T cell lymphoma [AITL] and natural killer [NK]/T cell lymphoma) [3].
Brentuximab vedotin, a CD30-directed antibody-drug conjugate, was recently reported for a promising efficacy in CD30-expressing systemic r/r anaplastic large cell lymphoma (ALCL) with an ORR of 86% and duration of response (DOR) of 12.6 months [17]. Some evidence indicated that brentuximab vedotin could also bring clinical benefit to CD30-positive PTCL-NOS patients, not other subtypes of PTCL [18]. The unmet medical needs remain as new drugs for other targets to be explored and possibility to improve the treatment paradigm for r/r PTCL.
In the past several years, immune checkpoint inhibitor (ICI) has revolutionized the clinical management of cancer [19]. The activity of anti-programmed cell death protein-1 (PD-1) has been observed in r/r classic Hodgkin lymphoma and primary mediastinal large B cell lymphoma, in which programmed death-ligand 1 (PD-L1) upregulation is commonly seen [20][21][22][23][24]. Nevertheless, in r/r diffuse large B cell lymphoma (DLBCL), nivolumab showed limited efficacy with an independently assessed ORR of 10% and 3% in the ASCT-failed cohort and ASCT-ineligible cohort, respectively [25].
For T cell lymphoma, anti-PD-1 antibodies have shown modest efficacy in r/r PTCL, but results were limited by a small sample size and concerns of rapid disease progression [26,27]. Thus, a better understanding of anti-PD-1 treatment for r/r PTCL patients and identification of biomarkers for immunotherapy optimization are required.
Geptanolimab (GB226) is a recombinant anti-PD-1 humanized monoclonal antibody that selectively blocks the interaction of PD-1 with its ligands, manufactured by Genor Biopharma Co., Ltd (Shanghai, China). Based on the phase 1 study of geptanolimab in lymphoma and advanced solid tumors (data not published), 3 mg/kg every 2 weeks was selected as recommended. Herein, we present the results of this phase 2 study (Gxplore-002) to determine the efficacy and safety of geptanolimab in patients with r/r PTCL, and assess the possible correlation between PD-L1 expression and its clinical outcome (NCT03502629).

Patients
Eligible individuals were patients aged 18 years and older with histologically confirmed PTCL, who had failed at least one prior systemic therapy. Additional criteria of enrolment included at least one bidimensionally measurable lesion according to investigator assessment as defined by Lugano criteria [28], an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, life expectancy of at least 3 months and at least 4 weeks after ASCT or major operation. Patients were also required to have adequate organ functions: absolute neutrophil count ≥ 1.0 × 10 9 /L, platelet count ≥ 75 × 10 9 /L, hemoglobin ≥ 80 g/L, total bilirubin ≤ 1.5 × the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (if liver involvements are present, ALT and AST up to 5 × ULN), serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (calculated by Cockcroft and Gault equation).
Patients were excluded if histologically classified as adult T cell leukemia/lymphoma (ATLL) or AITL; concomitant receipt of immunosuppressive therapy; prior exposure to any anti-PD-1/PD-L1 or anti-cytolytic T lymphocyte-associated antigen-4 (CTLA-4) antibody; treatment with systematic corticosteroids (> 10 mg daily prednisone equivalent) within 2 weeks; active or history of autoimmune disease except for type I diabetes, controllable hypothyroidism with replacement treatment, controllable skin disorders without systematic treatment, celiac disease within control; human immunodeficiency virus (HIV) infection, anti-treponema pallidum antibody (TP-Ab) positive or active hepatitis B or C; use of any investigational agent, biologics or devices within 30 days (or at least five periods of half-life) before study treatment. Pathological diagnosis was done by study site pathologists for study enrolment, and patient eligibility was determined by site investigators. Central pathology review was conducted retrospectively upon patient consent.
The study was done in accordance with the Declaration of Helsinki and International Council for Harmonisation (ICH) guidelines for Good Clinical Practice. The study protocol is available in Additional file 1. The protocol, protocol amendments and patient informed consent were reviewed and approved by the relevant independent ethics committee at each participating study site prior to implementation. Written informed consent was obtained from all patients prior to enrolment.

Study design, treatment and assessment
We conducted this open-label, single-arm, phase 2 study across 41 sites in China to evaluate the activity and safety profile of geptanolimab in r/r PTCL. Eligible patient received geptanolimab intravenously at a dose of 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity, withdrawal of consent or end of the study (i.e., a maximum treatment duration of 2 years of the last subject, termination of treatment, consent withdrawal, lost to follow-up or death, whichever occurs first). Geptanolimab treatment was permitted to continue beyond the first assessment of progressive disease (PD) if the patient could benefit from the treatment with acceptable toxicity assessed by the investigator. Dose modification was not allowed. Patients with dose interruptions for more than 4 weeks should permanently discontinue the treatment.
Treatment response was assessed every 6 weeks until week 48 and every 12 weeks thereafter during the treatment phase. Treatment response was assessed using computed tomography (CT) or magnetic resonance imaging (MRI) and complementary information from positron emissions tomography and computed tomography (PET-CT). PET-CT was performed at baseline, week 13 and termination of treatment. All radiographic records of enrolled patients were provided to independent radiological review committee (IRRC). Efficacy was assessed based on individual best objective response by both investigators and IRRC according to the Lugano criteria [28]. Survival follow-up was done every 3 months until patient death, lost to follow-up or the end of the study.

Outcomes
The primary endpoint of this study was ORR, defined as the proportion of patients with a best overall response (including complete response [CR] and partial response [PR]) per the Lugano criteria and assessed by IRRC. The secondary outcomes included disease control rate (DCR), time to response (TTR), duration of response (DOR), PFS, OS, safety and immunogenicity of geptanolimab.
Safety was monitored for 30 days from the last dose of geptanolimab for all patients or before any anticancer therapy began. If no new anticancer treatment has commenced, the safety follow-up should be repeated as far as possible for 90 days after the last dose of geptanolimab. Adverse events (AEs) were assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), version 4.03 and classified as related, possibly related, unlikely related, unrelated and uncertainly related to treatment assessed by investigator. Treatment-related AEs (TRAEs) were those AEs labeled related, possibly related, or uncertainly related to study drug. As an ICI, geptanolimab could cause a spectrum of immune-related adverse events (irAEs), which is recognized and managed according to National Comprehensive Cancer Network guideline for Management of Immunotherapy-Related Toxicities [29].

Statistical analysis
To provide roughly 85% power to reject the null hypothesis that the true proportion of patients achieving an objective response is 15% or fewer and given a one-sided alpha of 2.5%, 73 patients were required. Considering the possible drop-off rate of 15%, at least 86 patients were to be recruited.
All patients receiving at least one dose of geptanolimab were included in the safety analysis set. Patients with retrospectively histological confirmation per central pathology review (n = 89) entered the full analysis set (FAS).
Efficacy analysis was performed in FAS and per protocol set (PPS), assessed by IRRC and by investigators. ORR was the proportion of patients with CR or PR as the best overall response. DCR was the percentage of patients achieving either a CR or PR or SD. We summarized AEs as the proportion of the total number of patients receiving at least one dose of geptanolimab.
Exact binominal confidence intervals (CIs) were calculated for response outcomes. PFS (from first geptanolimab administration to progression or death, whichever occurs first), OS (from first geptanolimab administration to death), DOR (from the date of first documented response to the date of first documented disease progression or death from any cause) and TTR (time from first geptanolimab administration to first documentation of response) were assessed using the Kaplan-Meier method. All statistical analyses were performed by using SAS version 9.4. This trial was registered at the ClinicalTrials.gov (NCT03502629).

Biomarker assessment
Immunogenicity was evaluated by the number of patients with antidrug antibody (ADA) positive. Serum samples were collected at baseline, week 1, 2, 6 and followed by every six weeks. An immunological ligand-binding assay (LBA) was developed and validated for the detection and quantitation of anti-geptanolimab antibodies in serum collected.
Archival tumor tissues were required from all patients prior to treatment. PD-L1 immunohistochemistry (IHC) was assessed on formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples using Ventana PD-L1 (SP263; Roche) rabbit monoclonal primary antibody for exploratory analysis. Measure of PD-L1 expression built on the estimated percentage of PD-L1-stained cells. Genomic DNA was extracted from FFPE tumor samples using ReliaPrep FFPE gDNA Miniprep System (Promega) following the manufacturer's instructions. Microsatellite instability (MSI) analysis using MSI Analysis System version 1.2 (Promega) and tumor mutation burden (TMB) assessed with hybridization capture of exons from 440 cancer-related genes were performed (Details in Additional file 1).

Patients and treatment
A total of 102 patients were recruited in this study at 41 sites in China from July 12, 2018, to August 15, 2019 (Additional file 1: Table S1). The average time for enrolled patients after the initial diagnosis of PTCL was 0.94 years (standard deviation: 1.53), and 58.8% of them had two or more prior treatments. At study entry, 84 (82.4%) patients had advanced disease and 13 (12.7%) patients had bone marrow involvement at baseline. All patients had received prior systematic treatment. For patients diagnosed with extranodal NK/T cell lymphoma, nasal type (ENKTL), 21 (91.3%) out of 23 patients received prior asparaginase-based chemotherapy. For other subtypes of PTCL except for ENKTL, 77 (97.5%) out of 79 patients were previously treated with anthracyclinecontaining chemotherapy. Twenty-four (23.5%) patients had received chidamide; 7 (6.9%) had undergone ASCT. Baseline characteristics of the 102 patients are shown in Table 1. Collectively, 89 patients with retrospectively histological confirmation per central pathology review were included in FAS (Additional file 1: Table S2). Of them, the most common histological subtypes were PTCL-NOS (n = 28 [31.5%]), ENKTL (n = 19 [21.3%]), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALCL ALK-, n = 13 [14.6%]) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALCL ALK+, n = 7 [7.9%]). At the cutoff date, 54 (52.9%) deaths were recorded and 13 (12.7%) patients were still under treatment (Fig. 2a). Disease progression was the most common reason for patient withdrawal, occurring in 50 (49.0%) patients. Eleven (10.8%) patients discontinued for TRAEs including two platelet count decreased, two autoimmune hemolytic anemia and two pneumonitis (Additional file 1: Table S3). All 102 patients were included in safety analysis and 89 with histological confirmation of PTCL were in FAS for efficacy analysis (Fig. 1).

Efficacy
As of August 15, 2020, the median follow-up was 4.06 (range 0.30-22.9) months. Efficacy data in the total enrolled population (n = 102) and FAS (n = 89) are presented in Table 2, with no significant difference observed between the two sets. Of FAS population, 36 of 89 (40.4%, 95% CI, 30.2% to 51.4%) patients achieved an overall response by IRRC with a median TTR of 1.4 (95% CI, 1.4 to 1.5) months for responders; disease control was achieved in 53 (59.6%; 95% CI, 48.6% to 69.8%) patients. Assessed by investigators, 34 of 89 (38.2%, 95% CI, 28.1% to 49.1%) achieved an overall response ( Table 2). The lower limit of the 95% CI (30.2%) of ORR by IRRC was above the prespecified threshold of response. Best reductions from baseline in tumor burden are shown in Fig. 2b.

Biomarker analysis
Of 94 patients with ADA samples available, two (2.1%) were tested positive for ADAs at baseline and one of them changed to be negative after geptanolimab administration. ADAs were detected in another four (4.3%) patients during treatment course. Archival FFPE tissue samples were obtained for TMB (n = 59) and MSI testing (n = 67). Most patients (n = 65, 97.0%) were microsatellite stable (MSS), and the median TMB was 1.

Discussion
Studies in r/r PTCL patients of second or later line treatment had a response rate ranging from 23 to 29% except brentuximab vedotin with a higher rate in CD30-positive PTCLs. In this study, treatment of geptanolimab demonstrated an IRRC assessed ORR of 40.4% in r/r PTCL. A subgroup analysis showed direct association of response and survival with PD-L1 ≥ 50% patients. To the best of our knowledge, this study represents the largest prospective clinical trial evaluating efficacy and safety of PD-1 inhibitor in PTCL patients. PD-L1 expression has been approved in many indications as a determinative biomarker for conducting anti-PD-1/PD-L1 treatment. Compared to DLBCL NOS, PD-L1 expression was higher in PTCLs [30], suggesting the possibility of adopting anti-PD-1 treatment in T and NK cell malignancies.
Preclinical data reported by Wartewig T et al. suggested that the oncogenic T cell signalling upregulated PD-1 expression while PD-1 suppressed oncogenic effector pathways. Additionally, their study found that ICIs could accelerate and/or reactivate T cell clones with oncogenically activated T cell receptor pathways, thus indicated the need for special consideration of using ICIs in patients with T cell non-Hodgkin lymphoma [31].
Some results of clinical studies indicated the concern of using PD-1 antibody in T cell lymphoma patients which might accelerate the tumor progression. A phase 2 study investigating nivolumab in ATLL, an aggressive mature T cell lymphoma characterized by human T cell leukemia virus type 1 (HTLV-1), discontinued after the first three patients showed a rapid progression by the first dose [32]. Further mechanism study suggested the detrimental effects derived from the correlation of PD-1 signaling and HTLV-1 basic zipper protein. In this study, we have excluded ATLL patients to avoid the possibility of rapid progression. In addition, a previous study of nivolumab in patients with r/r PTCL, in which half of patients (6/12) were AITL, reported hyperprogressive disease in four Table 2 Efficacy of geptanolimab ORR, objective response rate; DCR, disease control rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; IRRC, independent radiological review committee; DOR, duration of response; CI, confidence interval; NR, not reached # 21 patients had confirmed progressive disease; 11 patients with a first progressive disease and still under treatment & 23 patients had confirmed progressive disease; 14 patients with a first progressive disease and still under treatment § Patients did not have post-baseline efficacy evaluation due to early termination or protocol violation  patients [27]. Thus, we initially excluded AITL as well from enrolling in this study. Nevertheless, four patients were retrospectively confirmed AITL per central pathology review and all of them had disease control including 2 PR and 2 SD. No hyperprogressive disease was observed in these four patients. Therefore, the efficacy and safety of anti-PD-1 treatment in AITL merit further investigations.
Other clinical data in PTCLs showed some activity. A phase 2 study of 23 enrolments with nivolumab treatment in T cell lymphoma represented an ORR of 17% in which all responders achieved PR. Two patients with PTCLs had response durations of 10.6 and 78.6+ weeks [33]. One more recent phase 2 trial of pembrolizumab monotherapy in r/r mature T cell lymphoma showed an ORR of 33% (5 of 15 patients) but halted after interim futility analysis [26]. The ORR of this study was 40.4%. Moreover, among the IRRC-assessed responders, the 12-month DOR rate was 48.5%, suggesting the survival benefit of geptanolimab for r/r PTCLs. Two patients in this study recorded an increased tumor burden over 200% compared to baseline. The possibility of hyperprogression has been ruled out and determined as disease progression by the investigators. In this study, the PD-L1 ≥ 50% rate was higher in patients with ENKTL (78.9%, 15/19) and ALCL ALK + (71.4%, 5/7), followed by ALCL ALK-(38.5%, 5/13) and PTCL-NOS (35.7%, 10/28). For B cell lymphomas with PD-L1 gene alteration and upregulation, response rate was higher with anti-PD-1 treatment [20][21][22][23][24]. We observed the correlation of PD-L1 expression with efficacy for PTCL patients in this study. Patients with PD-L1 expression of 50% or higher (n = 45) derived more benefit from geptanolimab treatment, showing an ORR of 53.3% and a median PFS of 6.2 months. Additionally, response rate was higher for patients with ENKTL, ALCL ALK-or ALCL ALK + . The associations between PD-L1 expression, pathological subtypes and response to geptanolimab need further exploration in future clinical studies of PTCLs.
The safety profile of geptanolimab is similar to previous report of geptanolimab and other anti-PD-1 antibodies with hematologic disorders seeming to be more common [26,27,34]. Although TRAEs including fatigue, gastrointestinal, skin disorders and pneumonitis were observed with anti-PD-1 treatment, the safety profile could vary in different malignancies [35,36]. Patients with PTCLs are heterogenous and aggressive, likely to be treated with intensive chemotherapy previously; thus, patients with r/r PTCL were more vulnerable to treatment. In this study, the most commonly reported grade 3 or 4 TRAEs were hematological, with lymphocyte count decreased and platelet count decreased reported in seven patients, and all cases are manageable. Limitation of this study included absence of central pathology review in other 13 patients. In addition, this study is single arm, and the follow-up period was short. Therefore, a randomized control trial with longer followup period is warranted to further investigate the treatment in this population.

Conclusions
In conclusion, geptanolimab showed promising activity and manageable toxicity for patients with r/r PTCL. Given this result, anti-PD-1 antibody could be a new treatment approach for patients with r/r PTCL.

Supplementary information
The online version contains supplementary material available at https ://doi. org/10.1186/s1304 5-021-01033 -1.   Fig. 4 a Post-hoc analysis of objective response rate and b Kaplan-Meier estimated of progression-free survival by PD-L1 expression based on an independent radiological review committee assessment. PD-L1, programmed death-ligand 1; CI, confidence interval; NR, not reached. Note Responders were response-evaluable patients with PD-L1 assessed who achieved a complete or partial response as best overall response per 2014 Lugano lymphoma response criteria. PD-L1 expression was assessed with a cutoff of 50%